Stability of ligand-binding domain dimer assembly controls kainate receptor desensitization

Journal Article · Wed Jun 17 04:00:00 EDT 2009 · EMBO J.

DOI:https://doi.org/10.1038/emboj.2009.86· OSTI ID:1005655

Chaudhry, Charu; Weston, Matthew C; Schuck, Peter; Rosenmund, Christian; Mayer, Mark L

AMPA and kainate receptors mediate fast synaptic transmission. AMPA receptor ligand-binding domains form dimers, which are key functional units controlling ion-channel activation and desensitization. Dimer stability is inversely related to the rate and extent of desensitization. Kainate and AMPA receptors share common structural elements, but functional measurements suggest that subunit assembly and gating differs between these subtypes. To investigate this, we constructed a library of GluR6 kainate receptor mutants and directly measured changes in kainate receptor dimer stability by analytical ultracentrifugation, which, combined with electrophysiological experiments, revealed an inverse correlation between dimer stability and the rate of desensitization. We solved crystal structures for a series of five GluR6 mutants, to understand the molecular mechanisms for dimer stabilization. We demonstrate that the desensitized state of kainate receptors acts as a deep energy well offsetting the stabilizing effects of dimer interface mutants, and that the deactivation of kainate receptor responses is dominated by entry into desensitized states. Our results show how neurotransmitter receptors with similar structures and gating mechanisms can exhibit strikingly different functional properties.

• Research Organization: Argonne National Laboratory (ANL)
• Sponsoring Organization: USDOE
• OSTI ID: 1005655
• Journal Information: EMBO J., Journal Name: EMBO J. Journal Issue: (10) ; 2009 Vol. 28; ISSN EMJODG; ISSN 0261-4189
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

36 MATERIALS SCIENCE
CORRELATIONS
CRYSTAL STRUCTURE
DEACTIVATION
DIMERS
ELEMENTS
FUNCTIONALS
INTERFACES
MUTANTS
RECEPTORS
STABILITY
STABILIZATION
TRANSMISSION
ULTRACENTRIFUGATION